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Nucleic Acids Research, 2000, Vol. 28, No. 21 4244-4253
© 2000 Oxford University Press

A novel form of intercalation involving four DNA duplexes in an acridine-4-carboxamide complex of d(CGTACG)2

Adrienne Adams*, J. Mitchell Guss, Charles A. Collyer, William A. Denny1 and Laurence P. G. Wakelin2

Department of Biochemistry, University of Sydney, NSW 2006, Australia, 1Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand and 2School of Physiology and Pharmacology, University of New South Wales, NSW 2052, Australia

The structures of the complexes formed between 9-amino-[N-(2-dimethyl-amino)butyl]acridine-4-carboxamide and d(CG5BrUACG)2 and d(CGTACG)2 have been solved by X-ray crystallography using MAD phasing methodology and refined to a resolution of 1.6 Å. The complexes crystallised in space group C222. An asymmetric unit in the brominated complex comprises two strands of DNA, one disordered drug molecule, two cobalt (II) ions and 19 water molecules (31 in the native complex). Asymmetric units in the native complex also contain a sodium ion. The structures exhibit novel features not previously observed in crystals of DNA/drug complexes. The DNA helices stack in continuous columns with their central 4 bp adopting a B-like motif. However, despite being a palindromic sequence, the terminal GC base pairs engage in quite different interactions. At one end of the duplex there is a CpG dinucleotide overlap modified by ligand intercalation and terminal cytosine exchange between symmetry-related duplexes. A novel intercalation complex is formed involving four DNA duplexes, four ligand molecules and two pairs of base tetrads. The other end of the DNA is frayed with the terminal guanine lying in the minor groove of the next duplex in the column. The structure is stabilised by guanine N7/cobalt (II) coordination. We discuss our findings with respect to the effects of packing forces on DNA crystal structure, and the potential effects of intercalating agents on biochemical processes involving DNA quadruplexes and strand exchanges. NDB accession numbers: DD0032 (brominated) and DD0033 (native).

* To whom correspondence should be addressed. Tel: +61 2 9351 7817; Fax: +61 2 9351 4726; Email: a.adams@bioch.usyd.edu.au


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